PROJECT SUMMARY Chronic inflammation in the gastrointestinal tract promotes the development of premalignant lesions imbued with potential devastating consequences. Defining the precise molecular mediators that collaborate with inflammation to endorse premalignancy will inform the design of effective prevention strategies. Genomic annotation of premalignant gastroesophageal (GE) lesions revealed that TP53 mutations occur frequently and predict the progression to cancer. Based on these observations, we hypothesize that chronic inflammation provides a selective advantage for GE cells harboring TP53 mutations to generate premalignant disease. The objective of this mentored research career development proposal is to combine our recent findings in cancer genomics with novel mouse models of inflammation to derive new conceptual insights into the premalignant state. To this end, we have designed an experimental system that integrates TP53 alterations in GE cells with two modes of inflammation using a novel mouse model (Aim 1). By labeling TP53 mutant GE cells with fluorescent probes, we will be able to track the evolution of premalignant disease in the setting of inflammation. Furthermore, direct analysis of premalignant lesions from these studies will help elucidate specific mutations and/or pathways that enable a selective advantage for TP53 mutant GE cells. We will also utilize an in vitro system to systematically test the impact of disease-relevant inflammation-associated factors on cellular functions of TP53 altered GE cells (Aim 2). Our preliminary data showed that deletion of TP53 in premalignant GE cells stimulates the production of inflammatory cytokines, implicating a potential vicious feedback cycle. Using a complement of mouse models, organoid culture, and patient samples, we will investigate the functional significance of inflammation pathways induced by TP53 alterations in premalignant GE lesions (Aim 3). Overall, these studies hold tremendous promise for cancer prevention in GE premalignancy. I am a medical oncologist with a research background in cellular and molecular biology. My long-term goal is to become a tenure-track independent laboratory investigator with expertise in gastrointestinal diseases. I am dedicated to leading a basic and translational research laboratory that defines key functional mechanisms of premalignant gastrointestinal disease with an emphasis on inflammation, genomics, and therapeutics. During my proposed training period, I will perform mentored research in the laboratory of Dr. Adam Bass at the Dana-Farber Cancer Institute. I am fortunate to have an exceptional advisory committee to help guide my research and career development including Dr. William Kaelin, Dr. Benjamin Ebert, Dr. Timothy Wang, Dr. Anil Rustgi, and Dr. Kevin Haigis. Coupled with an outstanding institutional environment, training plan, and career development program, the proposed research will enable me to achieve my long-term career aspirations.